Renal Control of Body Fluid Volume and Circulatory Dynamics

该计划项目的一个主要主题是肾体液反馈控制系统，其中 肾脏在体液容量和动脉压的长期调节中起着主导作用。一个 迄今在所有形式的高血压检查中发现的常见肾脏异常，包括遗传性高血压 而实验模型和人类原发性高血压是高血压的一种转换压钠排泄 两性关系。项目II“的一个主要目标是研究内皮素、一氧化氮、 氧化应激和新的抗血管生成因子介导的肾压性钠尿降低 与内皮功能障碍相关的特殊形式的高血压先兆子痫(PE)。高血压 与PE相关的疾病在怀孕期间发生，分娩后缓解，涉及胎盘为中枢 疾病的罪魁祸首。据推测，PE的启动事件涉及胎盘灌注量的减少，从而导致 导致广泛的母体血管内皮功能障碍的机制尚待阐明。近期 对先兆子痫妇女的研究表明，胎盘和循环中的 天然存在的血管内皮生长因子拮抗剂--可溶性FMS样酪氨酸激酶-1 血管内皮生长因子(VEGF)和胎盘生长因子(PIGF)。先兆子痫患者sFlt-1升高与降低有关 血浆游离血管内皮生长因子和前列环素。此外，腺病毒介导的sFlt-1在妊娠大鼠体内的应用 先兆子痫妇女血浆浓度降低，游离血管内皮生长因子和PIGF减少并产生 高血压和蛋白尿。尽管这些新的发现表明sFlt-1参与了慢性粒细胞白血病的发病机制 高血压在子痫前期，目前尚不清楚的是导致sFlt-1过量的具体机制。 1产生和sFlt-1在妊娠期升高血压的机制。基于我们的 初步数据，我们建议检验降低子宫灌注压(RUPP)的中心假说 孕鼠通过血管紧张素Ⅱ和肿瘤坏死因子-ct依赖机制增加胎盘sflt-1。这一增长 SFlt-1的血浆浓度反过来会导致血浆中VEGF和PIGF的浓度降低。在……里面 此外，我们认为妊娠期慢性sflt-1过量会损害肾功能，增加总 通过降低血浆游离血管内皮生长因子和前列环素浓度来降低外周阻力和血压 促进内皮细胞功能障碍，表现为ET-1、ROS的产生增加和NO的减少。 为了验证这一假说，我们将对动脉压、肾脏、激素和内皮因子进行检测。 长期RUPP所致的清醒、慢性器质性PE大鼠模型。除了Rupp之外 模型中，将使用sFlt-1的PE模型来确定sflt-1与ET-1、ROS和NO之间的相互作用 生产，而体外胎盘外植体模型将被用来检查直接相互作用 缺氧与胎盘sFlt-1、AngII和TNF-a的产生。

A major theme of this Program Project has been the renal-body fluid feedback control system in which the kidneys play a dominant role in the long-term regulation of body fluid volumes and arterial pressure. A common renal abnormality that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension is a hypertensive shift in the pressure natriuresis relationship. A major objective of Project II "is to examine the interactions between endothelin, nitric oxide, oxidative stress and novel anti-angiogenic factors in mediating the reduction in renal-pressure natriuresis in a specific form of hypertension associated with endothelial dysfunctionpreeclampsia (PE). Hypertension associated with PE develops during pregnancy and remits after parturition implicating the placenta as a central culprit in the disease. The initiating event in PE is postulated to involve reduced placental perfusion that leads to widespread maternal vascular endothelial dysfunction by mechanisms that remain to be elucidated. Recent studies in preeclamptic women have demonstrated increased placental and circulating concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), a naturally occurring antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Increased sFlt-1 during preeclampsia is associated with decreased free plasma VEGF and PIGF. Moreover, adenovirus mediated administration of sFlt-1 to pregnant rats to mimic plasma concentrations observed in preeclamptic women, decreases free VEGF and PIGF and produces hypertension and proteinuria. Although these novel findings implicate sFlt-1 in the pathogenesis of hypertension during preeclampsia, what remains unclear are the specific mechanisms that lead to excess sFlt- 1 production and the mechanisms whereby sFlt-1 increases blood pressure during pregnancy. Based on our preliminary data, we propose to test the central hypothesis that reduced uterine perfusion pressure (RUPP) in the pregnant rat increases placental sFlt-1 via ANGII and TNF-ct dependent mechanisms. The increase in plasma concentration of sFlt-1, in turn results in decreased plasma concentrations of VEGF and PIGF. In addition, we propose that chronic sFlt-1 excess during pregnancy impairs renal function and increases total peripheral resistance and blood pressure by decreasing plasma concentrations of free VEGF and PIGF which contribute to endothelial cell dysfunction marked by enhanced production of ET-1, ROS and decreased NO. To test this hypothesis arterial pressure, renal, hormonal, and endothelial factors will be examined in a conscious, chronically instrumented rat model of PE produced by long-term RUPP. In addition to the RUPP model, a sFlt-1 model of PE will be used to determine the interaction between sFlt-1 and ET-1, ROS, and NO production while an in vitro placental explant model will be used to examine the direct interaction between hypoxia and placental sFlt-1, ANGII, and TNF-a production.